SI9600186A - Tricyclic 5,6-dihydro-9h-pyrazolo (3,4-c)-1,2,4-triazolo (4,3-alpha) pyridines - Google Patents

Abstract

A compound of formula (I), wherein R<1>, R<2>, R<3>, R<9> and R<10> are as defined in the description. The compound of formula (I) and the pharmaceutically acceptable salts thereof are useful in inhibiting phosphodiesterase (PDE) Type IV and the production of tumor necrosis factor (TNF) and in the treatment of asthma, arthritis, bronchitis, chronic obstructive airways disease, psoriasis, allergic rhinitis, dermatitis and other inflammatory diseases characterized by phosphodiesterase (PDE) Type IV activity as well as AIDS, sepsis, septic shock and other diseases, such as cachexia, involving the production of TNF.

Description

The present invention relates to tricyclic 5,6-dihydro-9H-pyrazolo [3,4-c] 1,2,4-triazolo [4,3-d] pyridines, which are selective phosphodiesterase (PDE) type IV inhibitors or inhibitors productions of tumor necrosis factor (TNF) and as such are useful in the treatment of asthma, arthritis, bronchitis, chronic obstructive airways disease, psoriasis, allergic rhinitis, dermatitis and other inflammatory diseases, as well as AIDS, sepsis, septic shocks and other diseases such as cachexia characterized by TNF secretion. The compounds of this invention may have a combined inhibitory effect on PDE IV and TNF.

The present invention also relates to methods of using these compounds and pharmaceutical compositions for the treatment of the above-mentioned diseases in mammals, in particular in humans.

Considering that cyclic AMP is a second intracellular carrier (E.V.Sutherland and T.W.Rall,

Pharmacol.Rev., 1960, 12,265), the inhibition of phosphorodiesterase has been the goal of adaptation and therefore has a therapeutic effect on the disease course. Recently, distinct classes of PDE have been discovered (J.A.Bravo and D.H.Reifsnyder, TiPS, 1990,11,150) and their selective inhibition leads us to improved pharmacological therapy (C.D.Nicholson, R.A.Challis, and M.Shadid, TiPS, 1991,12,19). Specifically, they have found that inhibition of type IV PDE can lead to inhibition of inflammatory mediator release (M.W.Verghese et.al.,

J.Mol.Celi Cardiol., 1989,12 (Suppl.II), S 61) and airway smooth muscle relaxation (TJTorphy, Directions for Nav / AntiAsthma Drugs, eds SROOonnell and CGPersson, 1988,37, Birkhauser- Verlag). Thus, compounds that inhibit type IV PDE but have a weak effect against other types of PDE, inhibit the release of inflammatory mediators and release airway smooth muscle, with no effect on the cardiovascular system or antiplatelary effects.

TNF has been found to be involved in many infectious and autoimmune diseases, including cachexia (Vi.Friers, FEBS Letters, 1991,285,199). TNF has also been shown to be a major mediator of inflammatory responses such as sepsis and septic shocks (C.E.Spooner et al., Clinical Immunology and Immunopathology, 1992,62, Sil).

SUMMARY OF THE INVENTION

The present invention relates to compounds of formula I

and pharmaceutically acceptable salts thereof; characterized by R ¹ being hydrogen, (C 1 -C ₆ ) alkyl, (C 1 -C ₆ ) alkoxy, (C 1 -C ₆ ) -alkenyl, phenyl, dimethylamino, (C ₃ -C ₆ ) cycloalkyl, (C ₃ -C ₆ ) -cycloalkyl (C ₃ 3

C ₃ ) alkyl or (C 1 -C ₆ ) acyl, characterized in that the alkyl, phenyl or alkenyl group may be substituted by up to two hydroxy, (C _x -C ₃ ) alkyl or trifluoromethyl groups or by up to three halogens ;

R ² and R ³ are each independently selected from hydrogen, (C 1 -C 7) alkyl, (C 1 -C 7) alkoxy (C 1 -C 7) alkyl, (C 2 -Cx 4) alkenyl, (C 3 -C 7) cycloalkyl, (C 3 C 7) - cycloalkyl (Cx-C2) alkyl, saturated or unsaturated (C4C7) heterocyclic (CH2) n group, where n is 0, 1 or 2, and contains a heteroatom in one or two groups consisting of oxygen, sulfur, sulfonyl, nitrogen and NR ⁴ wherein R ^{4 is} hydrogen or (C ₁ -C ₄ ) alkyl; or a group of formula,

where a is an integer between 1 and 5; b and c are 0 or 1; R ⁵ is hydrogen, hydroxy, (C 1 -C 5) alkyl, (C 2 -C 5) alkenyl, (C 1 -C 5) -alkoxy, (C 3 -C 6) cycloalkoxy, halogen, trifluoromethyl, CO2R ⁶ , CONR ⁶ R ⁷ , NR ⁶ R ⁷ , NO 2 or SO ₂ NR ⁶ R ⁷ , wherein R ⁶ and R ^{7 are} each independently selected from hydrogen or (C 1 -C 4) alkyl; wherein Z is oxygen, sulfur, SO 2, CO or NR ⁸ wherein R ^{8 is} hydrogen or (C 1 -C 4) alkyl; and Y is (C 1 -C 5) alkylene or (C ₂ -C ₆ ) alkenyl optionally substituted by up to two (C 1 -C 7) alkyl or (C ₃ -C ₇ ) -cycloalkyl groups; wherein each alkyl, alkenyl, cycloalkyl, alkoxyalkyl or heterocyclic group may be substituted by one to fourteen, preferably one to five, of the groups consisting of (C _x -C ₂ ) alkyl, trifluoromethyl or halogen; and

R ⁹ and R ¹⁰ are each independently selected from the group consisting of hydrogen, (C 1 -C ₆ ) alkyl, (C 1 -C ₆ ) alkoxy, (C ₆ -C ₁₀ ) aryl and (C ₆ C 10) aryloxy.

The term alkyl as used herein means, unless otherwise indicated, saturated monovalent hydrocarbonate radicals having straight, branched or cyclic moieties or combinations thereof.

The term alkoxy as used herein includes O-alkyl groups, wherein alkyl is defined above.

The term tenyl as used herein is defined by thiophene-CH ₂ ~, unless otherwise indicated.

The term aryl as used herein, unless otherwise indicated, includes organic radical derivatives derived from aromatic hydrocarbon by removal of one hydrogen, such as phenyl or naphthyl, optionally substituted with one to three substituents independently selected from fluoro, chloro, cyano, nitro, trifluoromethyl, (C 1 -C ₆ ) alkoxy, (C ₆ -C ₁₀ ) -aryloxy, trifluoromethoxy, difluoromethoxy and (C 1 -C ₆ ) alkyl.

The term alkoxy as used herein includes O-aryl groups, with aryl defined above.

The term acyl as used herein, unless otherwise indicated, includes radicals of the general formula RCO, wherein R is alkyl, alkoxy, aryl, arylalkyl or arylalkyloxy and the terms alkyl or aryl as defined above.

Preferred are compounds of formula I wherein R ^{1 is} methyl, ethyl or isopropyl.

Other preferred compounds of formula I include those wherein R ^{3 is} (C 1 -C ₆ ) alkyl, (C ₂ -C ₆ ) alkenyl, (C ₃ -C ₇ ) -cycloalkyl, (C ₃ C ₇ ) -cycloalkyl (C 1 ~ C ₆ ) alkyl or phenyl, optionally substituted by one to two groups consisting of hydrogen, hydroxy, (C 1 -C 6)

C ₅ ) alkyl, (C ₂ -C ₅ ) -alkenyl, (C 1 -C 5) alkoxy, halogen, trifluoromethyl,

CO ₂ R ⁶ , CONR ⁶ R ⁷ , wherein R ⁶ and R ^{7 are} each independently hydrogen or (C ₂ C ₄ ) alkyl.

Specific preferred compounds of formula I include the following compounds:

9-cyclopentyl-5,6-dihydro-7-ethyl-3-phenyl-9H-pyrazolo [3,4-c] -1,2,4 triazolo [4,3-α] pyridine;

9-Cyclopentyl-5,6-dihydro-7-ethyl-3- (2-furan-2-yl) -9H-pyrazolo [3,4 c] -1,2,4-triazolo [4,3-α] pyridine;

9-Cyclopentyl-5,6-dihydro-7-ethyl-3- (2-pyridyl) -9H-pyrazolo [3,4-c]

1.2.4- triazolo [4,3-α] pyridine;

9-Cyclopentyl-5,6-dihydro-7-ethyl-3- (4-pyridyl) -9H-pyrazolo [3,4-c]

1.2.4-triazolo [4,3-a] pyridine;

9-cyclopentyl-5,6-dihydro-7-ethyl-3- (3-tenyl) -9H-pyrazolo [3,4-c] 1,2,4-triazolo [4,3-a] pyridine;

3-benzyl-9-cyclopentyl-5,6-dihydro-7-ethyl-9H-pyrazolo [3,4-c] 1,2,4-triazolo [4,3-α] pyridine;

9-cyclopentyl-5,6-dihydro-7-ethyl-3-propyl-9H-pyrazolo [3,4-c] 1,2,4-triazolo [4,3-α] pyridine;

3,9-dicyclopentyl-5,6-dihydro-7-ethyl-9H-pyrazolo [3,4-c] -1,2,4triazolo [4,3-α] pyridine;

9-Cyclopentyl-5,6-dihydro-7-ethyl-3- (1-methylcyclohex-1-yl) -9Hpyrazolo [3,4-c] -1,2,4-triazolo [4,3-α] pyridine ;

3- (t-butyl) -9-cyclopentyl-5,6-dihydro-7-ethyl-9H-pyrazolo- [3,4-c] 1,2,4-triazolo [4,3-α] pyridine;

9-cyclopentyl-5,6-dihydro-7-ethyl-3- (2-methylphenyl) -9H-pyrazolo [3,4 c] -1,2,4-triazolo [4,3-α] pyridine;

9-cyclopentyl-5,6-dihydro-7-ethyl-3- (2-methoxyphenyl) -9Hpyrazolo [3,4-c] -1,2,4-triazolo [4,3-α] pyridine;

9-cyclopentyl-5,6-dihydro-7-ethyl-3- (thien-2-yl) -9H-pyrazolo- [3,4c] -1,2,4-triazolo [4,3-α] pyridine;

3- (2-chlorophenyl) -9-cyclopentyl-5,6-dihydro-7-ethyl-9H-pyrazolo [3,4c] -1,2,4-triazolo [4,3-α] pyridine;

9-cyclopentyl-5,6-dihydro-7-ethyl-3- (iodophenyl) -9H-pyrazolo [3,4-c] 1,2,4-triazolo [4,3-α] pyridine;

9-Cyclopentyl-5,6-dihydro-7-ethyl-3- (2-trifluoromethylphenyl) -9Hpyrazolo [3,4-c] -1,2,4-triazolo [4,3-α] pyridine and

5,6-Dihydro-7-ethyl-9- (4-fluorophenyl) -3- (1-methylcyclohex-1-yl) -9Hpyrazolo [3,4-c] -1,2,4-triazolo [4,3 -α] pyridine.

The present invention also relates to methods of inhibiting type IV phosphodiesterases (PDEs) and the production of TNF-α, compounds of formula I, or pharmaceutically acceptable salts thereof, administered in an effective amount to a patient.

The present invention also relates to methods of treating inflammatory conditions in mammals by administering an anti-inflammatory amount of a compound of Formula I or pharmaceutically acceptable salts thereof.

The present invention also relates to pharmaceutical compositions for (a) treating asthma, arthritis, bronchitis, chronic obstructive airways disease, psoriasis, allergic rhinitis, dermatitis and other inflammatory diseases characterized by type IV phosphorodiesterase (PDE) activity, AIDS , sepsis, septic shock and other ailments such as cachexia involving TNF production; or (b) the inhibition of type IV phosphodiesterase and the production of TNF-α by an effective amount of a compound of formula I or its pharmaceutically acceptable salts together with a pharmaceutically acceptable carrier.

The present invention also relates to the treatment or prevention of conditions and diseases such as asthma, arthritis, bronchitis, chronic obstructive airways disease, psoriasis, allergic rhinitis, dermatitis and other inflammatory diseases, AIDS, septic shock and other diseases such as e.g. cachexia involving the production of TNF-α, with an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof.

DETAILED DESCRIPTION OF THE INVENTION

The following reaction scheme shows but is not limited to the preparation of the compounds of the present invention. Unless otherwise indicated in the reaction scheme and the discussion that follows, then R ¹ , R ² , R ³ , R ⁹ and R ¹⁰ are as defined above.

δ

PREPARATION 1

V

VI

PREPARATION 2

IX

PREPARATION 3

PREPARATION 4

XM

SCHEME 1

SCHEME 2

XI

In reaction 1 of preparation 1,2-pyrrolidinone the compound of formula III is converted to the corresponding N- (4-methoxyphenyl) -2-pyrrolidone compound of formula IV after reaction III with 4-iodoanisole or purified 4bromoanisole in the presence of copper and potassium carbonate. The reaction mixture is heated to a temperature between 110 and 170 ° C, preferably about 150 ° C, for 14 to 22 hours, preferably about 18 hours, under inert reaction conditions.

In reaction 2 of Preparation 2, R ¹ halide, where R ^{1 is} (C _x -C ₆ ) alkyl, is added to the magnesium suspension in an anhydrous aprotic solvent. The reaction mixture is heated at reflux temperature until all of the magnesium is consumed and cooled to a temperature between -15 ° C and 15 ° C, preferably about 0 ° C. N- (4-methoxyphenyl) -2-pyrrolidone compound of formula IV is then added and the reaction mixture is warmed to room temperature and stirred for at least 1.5 to 2.5 hours, preferably 2 hours. A suitable alkyl halide is bromomethane, bromoethane or bromopropane. Preferably the anhydrous aprotic solvent is anhydrous ether.

The desired intermediate is isolated and converted to the corresponding 1,2,5,6-tetrahydropyridine compound of formula V by dispersing the precipitate in a mixture of apolar aprotic solvent and base. Ethyl oxalyl chloride was added and the reaction mixture was heated at reflux for 1.5 to 4.5 hours, preferably 3.0 hours. It is best to use benzene and sodium hydroxide as a non-polar aprotic solvent. The solvents are removed and the resulting residue is treated with a solution of sodium alkoxide in ethanol. After one to three hours, preferably 1.5 hours at reflux, the mixture is concentrated under reduced pressure and acidified with HCl to a pH of about 3.

In reaction 3 of preparation 1, the compound of formula V is converted to the corresponding 3-methoxy-1,2,5,6-tetrahydropyridine compound of formula VI, with the reaction mixture of the compound of formula V and 3-methyl-lptolyltriazene in an aprotic solvent, preferably 1. 2-dichloroethane, heated to reflux temperature over a period of between half an hour and two hours, preferably about 45 minutes.

In reaction 1 of preparation 2, 1,2,5,6-tetrahydropyridine a compound of formula VII, wherein R ^{11 is} hydrogen or methyl, is converted to the corresponding 4,5,6,7-tetrahydro-1H-pyrazolo [3,4-c] a pyridine compound of formula VII by reacting this compound with a hydrazine compound of formula R ³ HNNH ₂ , wherein R ^{3 is as} defined above. Both derivatives of compounds of formula VII, 3-hydroxy and 3-methoxy can be used as starting compounds under one of three different series of reaction conditions.

Under the first of three reaction conditions of 1,2,5,6tetrahydropyridine, the compound of formula VII is converted to the corresponding compound of formula VII by reaction of this compound with hydrazine hydrochloride and sodium alkoxide in an anhydrous polar protic solvent. Preferred sodium alkoxide is sodium methoxide and the anhydrous polar protic solvent is anhydrous ethanol. The reaction mixture is heated at reflux temperature between 9 and 15 hours, preferably about 12 hours.

Under another set of reaction conditions, 1,2,5,6-tetrahydro-pyridine compound VII is converted to the corresponding compound of formula VIII by reaction of compound VII with hydrazine in an anhydrous polar protic solvent, preferably in ethanol. The reaction mixture is heated at reflux temperature between 16 and 24 hours, preferably about 20 hours.

Under a third series of reaction conditions of 1,2,5,6-tetrahydro-pyridine Compound VII is converted to the corresponding compound of formula VIII by reaction of compound VII with hydrazine or hydrazinc chloride in a polar protic solvent, preferably in methanol. The reaction mixture is heated at a temperature between 70 and 110 ° C, preferably about 90 ° C, under a gentle stream of nitrogen until the solvent is removed. The purified mixture is then heated at a temperature of 120 to 180 ° C, preferably at 150 ° C, for half an hour up to 90 minutes, preferably around one hour.

In reaction 2 of preparation 2, the compound of formula VIII is converted to the corresponding 6-H-4,5,6,7-tetrahydro-7-oxo-1H-pyrazolo [3,4-c] -pyridine compound of formula IX by reacting solution VIII in a polar aprotic solvent, preferably acetonitrile, with a solution of cerium (IV) ammonium nitrate in water, at a temperature between -15 and 15 ° C, preferably about 0 ° C, for 20 to 50 minutes, preferably for 35 minutes. After completion of the reaction, the mixture was diluted with water and extracted with ethyl acetate. The combined organic extracts were washed with saturated sodium bicarbonate and then with sodium sulfite.

In reaction 1 of preparation 3, a compound of formula XII, prepared as described in United States Patent 3,423,414, is converted to the corresponding compound of formula VIII, wherein R ^{1 is} dimethylamino, by treating compound XII with sodium hydride in a polar aprotic solvent such as tetrahydrofuran. at a temperature between 0 and 62 ° C, preferably about 25 ° C, for 1 to 6 hours, preferably for one hour. At room temperature, the reaction mixture was added with an excess of methyl iodide and allowed to stir for one to 24 hours, preferably 2 hours.

In reaction 2 of preparation 3, the compound of formula VIII is further reacted to give the corresponding 6-H-4,5,6,7-tetrahydro-7-oxolH-pyrazolo [3,4-c] pyridine compound of formula IX, wherein R ¹ dialkylamino, as described above, in reaction 2 of preparation 2.

In reaction 1 of preparation 4, the compound of formula XII is converted to the corresponding compound of formula XIII by reacting compound XII with bromotrimethylsilane and sodium nitrite in an aprotic solvent such as tetrachloride at a temperature between 0 and 25 ° C, preferably at 25 ° C and a time period between 6 and 48 hours, preferably 24 hours.

In reaction 2 of preparation 4, the compound of formula XIII is converted to the corresponding compound of formula VIII, wherein R ^{1 is} vinyl, by reacting compound XIII with vinylributyltin and a catalytic amount of tetrakis (triphenylphosphine) palladium (0) in a non-polar aprotic solvent such as benzene at a temperature of between 80 and 120 ° C, preferably at 100 ° C and a time period of 24 to 72 hours, preferably 48 hours.

In reaction 3 of preparation 3, the compound of formula VIII is further reacted to give the corresponding 6-H-4,5,6,7-tetrahydro-7-oxo-1 H -pyrazolo [3,4-c] pyridine compound of formula IX, wherein R ¹ alkenyl, according to the procedure described above, in reaction 2 of preparation 2.

In Scheme 1 reaction 1, the lactam compound of formula IX is converted to the corresponding thiolactam compound of formula X by reacting compound IX with phosphorus pentasulfide in a polar aprotic solvent such as 1,4-dioxane or pyridine. The reaction mixture is heated at reflux temperature for 12 to 48 hours, preferably 18 hours.

In reaction 2 of Scheme 1, the thiolactam X is converted to the corresponding tricyclic 5,6-dihydro-9H-pyrazolo [3,4-c] -1,2,4-triazolo- [4,3α] pyridine compound of formula I such that X is treated with anhydrous hydrazine in the presence of an anhydrous aprotic solvent such as pyridine under inert reaction conditions. The reaction mixture is heated to a temperature between 50 and 100 ° C, preferably 70 ° C, for 5 to 30 minutes, preferably for 5 minutes. The volatiles are removed under reduced pressure and a fresh anhydrous aprotic solvent, preferably pyridine, is added. This is followed by the addition of a suitable acid chloride of the formula R ² COC1, wherein R ^{2 is} defined above. The resulting reaction mixture was stirred for one to four hours, preferably about two hours. The volatiles are again removed under reduced pressure. The residue is dissolved in an aprotic solvent such as dimethylformamide and heated at reflux temperature for one to four hours, preferably two hours.

In reaction 1 of Scheme 2, the thiolactam of the compound of formula X is converted to the corresponding methylthio compound of formula XI, such that a mixture of X-a and silica gel in an aprotic solvent such as ether is treated with a solution of diazomethane in ether. The temperature of the reaction mixture should be between -5 and 10 ° C, preferably about 0 ° C, from half an hour to five hours, preferably one hour.

In reaction 2 of Scheme 2, the methylthio compound of formula XI is converted to the corresponding tricyclic 5,6-dihydro-9H-pyrazolo [3,4-c] -1,2,4triazolo- [4,3-α] pyridine compound of formula I, thus that XI is reacted with a hydrazide compound of formula R ² CONHNH ₂ or with a suitable hydrochloride salt in an aprotic solvent such as pyridine under inert reaction conditions. The reaction mixture is heated to a temperature between 120 and 150 ° C, preferably about 135 ° C, for 2 to 6 hours, preferably for 4 hours. The volatiles are then removed under reduced pressure and the resulting oil is further heated at a temperature between 135 and 165 ° C, preferably about 150 ° C, two to six, preferably four hours.

In Scheme 3 reaction 1, the compound of formula XIV is converted to the corresponding compound of formula XV, according to the procedure described in Canadian Journal of Chemistry, 33, 1714 (1955).

In Scheme 3 reaction 2, the compound of formula XV is converted to the corresponding compound of formula XVI, wherein R ^{12 is} (C 1 -C 8) alkyl by reacting compound XV with alkyl lithium, in a polar aprotic solvent such as ether, at a temperature of from -50 to - 80 ° C, preferably at -78 ° C, for a period of 15 minutes to two hours, preferably half an hour.

In reaction 3 of Scheme 3, the compound of formula XVI is converted to the corresponding 5,6-dihydro-9H-pyrazolo [3,4-c] -1,2,4-triazolo- [4,3-α] pyridine compound of formula I, where R ^{1 is} (C1-Cg) acyl, such that XVI is reacted with pyridinium chlorochromate in a non-polar aprotic solvent such as methylene chloride at room temperature for 6 to 24 hours, preferably for 12 hours.

The ability of the compounds or their pharmaceutically acceptable salts of phosphodisterase IV (PDE ₄ ) inhibition and their efficacy in the treatment of inflammatory diseases is demonstrated in the following in vitro assays.

BIOLOGICAL TESTS

Human eosinophil PDE «

Human peripheral blood was collected in ethylenediaminetetraacetic acid and diluted to 1: 2 in piperazine-N, N'-bi-2-ethane-sulfonic acid (PIPES) buffer and then applied to the percolated solution. Gradients are formed by centrifugation for 30 minutes at 2000 rpm and 4 ° C. The residue of the insulation process based on the procedure of Kita et al., Immunol., 152.5457 (1994) is carried out at 4 ° C. A neutrophil / eosinophilic vehicle is collected from the percolated gradient and red blood cells are lysed. The remaining cells were washed in PIPES (1% FCS), incubated for 1 hour with anti-CD16 micro-drops (MASC) and neutrophils were removed through a magnetic column. The eosinophils are collected in the eluent and analyzed with blue trypan for viability and purity by diff-quick stain analysis. The purity of eosinophils is usually greater than 99% using this method.

Purified eosinophils were resuspended in 750 pL PDE of lysis buffer (20mM triethylamine, 1mM ethylenediaminetetraacetic acid, 100 pg / mL bacitracin, 2mM benzamidine, 50 pM leupeptin, 50 pM PMSF, 100 pg / mL soybean trypsin viral trypsin). The cells are slowly thawed and sonicated. The membranes swirl (the tear is confirmed by Tripan blue particle stains). The pelleted cells were centrifuged at 45,000 rpm at 4 ° C to isolate the membranes. The cytosol is decanted and the membranes resuspended and used as the PDE source in the hydrolysis test.

The compounds were dissolved in 10-2M dimethyl sulfoxide, then diluted to 1:25 in water to 4X10 ~ ⁴ M. This suspension was diluted to 1:10 in 4% dimethyl sulfoxide to give the final dimethyl sulfoxide concentration in the test 1%.

PHOSPHODIESTERASE INHIBITION TEST

Put in a 12 X 75 mm glass tube:

pL PDE assay buffer 25 μϊ, 4 nM / mL cAMP gL test compound fxL PDE source (membrane)

Background control = boiling membrane for 10 minutes Positive control = 25 gL of unboiled membrane Incubated for 25 minutes at 37 ° C in a water bath.

The reaction was stopped by boiling the samples for 5 minutes. Samples were applied to an Affigel column (1 mL of volume) previously calibrated with 0.25 M acetic acid and 0.1 mM N- [2-hydroxyethyl] -piperazine-N'-2-ethanesulfonic acid (HEPES) / 0.1 mM NaCl buffer (pH 8.5). . The cAMP was washed from the column with HEPES / NaCl, the 5'-AMP was diluted with 4 mL of 0.25 M acetic acid. 1 mL of eluent was counted in 3 mL of scintillation fluid for 1 minute [3Η].

Substrate substitution = (cpm positive control X 4) / total activity. The replacement ratio must be between 3 and 15% for the experiment to be valid.

% inhibition = l- (eluted cpm background cpm / control cpm background cpm) x 100.

IC50 is obtained by linear regression of the inhibition of the titration curve (linear part) and expressed in μΜ.

TNF

The ability of the compounds or their pharmaceutically acceptable salts to inhibit TNF-α production and their efficacy in treating diseases involving TNF-α production are demonstrated in the following in vitro assays:

Peripheral blood (100 mls) of human volunteers was collected in ethylenediaminetetraacetic acid (EDTA). Mononuclear cells were isolated with Ficoll / Hypaque and washed three times in incomplete Hank's balanced salt solution (HBSS). The cells were resuspended at a final concentration of 1 X 10 ⁶ cells per mL in preheated RPMI (containing 5% FCS, glutamine, pen / step and nystatin). Monocysts were placed in 1 x 10 ^6-well plates in 1.0 mL into 24-well plates. The cells were incubated at 37 ° C (5% carbon dioxide) and allowed to adhere to the plates for 2 hours. After this time, the uncharged cells are removed by gentle washing. The test substance (10 µL) was added to the cells at 3-4 concentrations each and incubated for 1 hour. Lipopolysaccharides (LPS) (10 pL) are injected at appropriate doses. The plates were incubated overnight (18 hours) at 37 ° C. At the end of incubation, the TNF period is analyzed by ELISA (R&D Quantikine test). For each compound, an IC ₅₀ determination is made based on linear regression analysis.

Pharmaceutically acceptable salts, after addition of acid, of the compounds of the present invention include, but are not limited to, those formed with HCl, Hbr, HNO ₃ , H ₂ SO ₄ , H ₃ PO ₄ , CH ₃ SO ₃ H, p-CH ₃ C ₆ H ₄ SO ₃ H, CH ₃ CO ₂ H, gluconic acid, tartaric acid, malic acid and succinic acid. The pharmaceutically acceptable cationic salts of the compounds of formula I of the present invention wherein R ^{5 is} CO ₂ R ⁶ and R ⁶ is hydrogen include, but are not limited to, sodium, potassium, calcium, magnesium, ammonium, Ν, d'-dibenzylethylenediamine, Nmethylglucamine (meglumine), ethanolamine and diethanolamine.

For curative administration to humans or for the prophylactic treatment of inflammatory diseases, the oral dose of the compounds of Formula I and their pharmaceutically acceptable substances (hereinafter referred to as the active substances of the present invention) is usually in the range of 0.1 to 400 mg daily for the average adult patient (70 kg). Thus, for a typical adult patient, each tablet or capsule contains from 0.1 to 50 mg of active substance on a suitable, pharmaceutically acceptable carrier. Doses for intravenous administration range from 0.1 to 40 mg per dose. For administration to the nose or inhalation, doses are formulated as a 0.1 to 1% solution. In practice, physicians will determine the actual dose that will be most appropriate for an individual patient and will vary depending on the age, weight and reaction of each patient. The above doses are averages of individual cases and may, of course, be individual doses larger or smaller than those indicated and, as such, are also significant in the present invention.

Various, well known methods, including oral, parenteral and topical administration, may be used to administer these compounds to humans for the purpose of inhibiting TNF-α. Generally, the dose of substances administered orally ranges from 0.1 to 25 mg / kg body weight of the treated person per day, preferably from 0.3 to 5 mg / kg. The compounds of formula I can also be used topically, in the form of cream or ointment, in concentrations between 0.5 and 1%, most often applied twice or thrice daily to the affected sites. However, dose variations will always occur depending on the condition of the person being treated. The person responsible for the treatment will in each case determine the appropriate dose for the individual patient.

For use in humans, the active substances of the present invention may be administered alone, but are usually in admixture or combination with a pharmaceutical solvent or carrier selected according to the type of use and conventional pharmaceutical practice. For example, they may be administered orally in the form of excipient-containing tablets such as starch and lactose, or in the form of capsules or ovals, alone or with the addition of an excipient, or as elixirs and suspensions to which flavors and colorants are added. They can be injected parenterally; e.g. intravenously, intramoecularly or subcutaneously. For parenteral administration, it is best to use them as sterile aqueous solutions that may contain other substances; e.g. enough salt or glucose to make the solution isotonic.

This invention is illustrated in the following examples, but is not limited to their details. The starting materials used in Preparations 1-4 are prepared as described in PCT Publication WO 95/01980.

1-Cyclopentyl-4,5-dihydro-3-ethyl-7-methylthio-1H-pyrazolo- [3,4c] pyridine

The magnetic stirrer was stirred in a 500 mL conical flask of 1-cyclopentyl-3-ethyl-7-thio-4,5,6,7-tetrahydro-1H-pyrazolo [3,4c] pyridine (0.322 g), neutral silica gel (10 g), and ether (100 mL) and then cooled to 0 ° C. To this mixture was slowly added an excess of a solution of diazomethane in ether. When gas release occurs within an hour, the reaction is quenched with 1 drop of acetic acid, filtered and concentrated under reduced pressure to give a yellow oil. The oil was purified by chromatography on silica gel using 1: 4 ethyl acetate: hexane as eluent. This gives 0.232 g of a yellow oil. Calculated analysis results for C14H21N3S: C, 63.85; H, 8.04;

N, 15.94. Results: C, 64.01; H, 8.37; N, 15.71.

PREPARATION 2 1-cyclopentyl-3-ethyl-7-thio-4,5,6,7-tetrahydro-1H-pyrazolo- [3,4- c] pyridine

To a solution of 1-cyclopentyl-3-ethyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo [3,4-c] pyridine (10.0 g) in anhydrous 1,4-dioxane was added phosphorus pentasulfide (3.9 g) . After stirring for 12 hours, the mixture was cooled to room temperature and concentrated under reduced pressure. The resulting yellow oil was dissolved in methylene chloride and washed with water and brine, dried over sodium sulfate and concentrated under reduced pressure. The orange residue was purified by silica gel column chromatography using a gradient mixture of hexane in methylene chloride as the eluent. This gives 9.3 g of a yellow solid. T _this i152-153 ° C; calculated analysis results for Ci ₃ Hi ₉ N ₃ S: C, 62.63;

H, 7.68; N, 16.86. Results: C, 62.14; H, 7.51; N, 16.35.

PREPARATION 3 1-Cyclopentyl-3-ethyl-6- (4-methoxyphenyl) -7-oxo-4,5,5,7-tetrahydrol-pyrazolo [3,4-c] pyridine

A mixture of 3-methoxy-1- (3-methoxyphenyl) -2-oxo-4-propionyl-1,2,5,6tetrahydro-pyridine (0.49 g, 1.7 mmol), cyclopentylhydrazine hydrochloride (0.40 g) and sodium methoxide (46 mg , 0.85 mmol) is heated to reflux while stirring. After 16 hours, the mixture was concentrated under reduced pressure and chromatographed on a silica gel column using 1: 4 ethyl acetate: hexane as eluent. This gives a white solid. Recrystallization from ether gave a white needle product.

T _T ai = 64-65 ° C; MS m / z [Μ +] 340.2025;

HRMS [Μ +] 340.2046.

PREPARATION 4 1-cyclopentyl-3-ethyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo [3,4c] pyridine

Mixtures of 1-cyclopentyl-3-ethyl-6- (3-methoxyphenyl) -7-oxo-4,5,6,7tetrahydro-1H-pyrazolo [3,4-c] pyridine (2.58 g, 7.60 mmol) and acetonitrile ( 90 mL) while stirring at 0 ° C, a solution of ceriumammonium nitrate (12.5 g, 22.8 mmol) in water (110 mL) was added. After 35 minutes, the mixture was diluted with water (550 mL) and extracted with ethyl acetate (100 mL X 4). The combined organic extracts were washed with 50% saturated sodium bicarbonate (250 mL) and then with 10% sodium sulfite until the washed portion turned pale yellow. The organic layer was further washed with saturated bicarbonate and brine and treated with decolourising charcoal. After stirring for 30 minutes, the mixture was cooled over sodium sulfate, filtered through Celite and concentrated under reduced pressure. The brown residue was recrystallized from ether to give 0.814 g of a tan solid. T _mp = 143-145 ° C; MS [Μ / Ζ] 2340; ^X H NMR (250 Mhz, CDCl ₃ ) 1.21 (t, J = 7.6 Hz, 3H), 1.62-2.13 (m, 8H), 2.62 (q, J = 7.6 Hz, 2H), 2.73 (t, J = 6.8) Hz, 2H), 3.51 (dt, J = 2.7 and 6.8 Hz, 2H), 5.47 (s, 1H), 5.61 (pentet, J-7.7 Hz, 1H).

EXAMPLE 1

9-cyclopentyl-5,6-dihydro-7-ethyl-3- (3-pyridyl) -9H-pyrazolo- [3,4c] -1,2,4-triazolo [4,3-a] pyridine 1-cyclopentyl -4,5-Dihydro-3-ethyl-7-methylthio-1H-pyrazolo- [3,4-c] pyridine (0.036 g, 0.14 mmol) and nicotinic acid hydrazide (0.021 g, 0.15 mmol) were dissolved in anhydrous pyridine ( 5 mL), dried in a tube over a flame. A dried condenser is added to the furnace, which is sealed and has an external guide. Using a long stainless steel needle, penetrate the septa and the center of the condenser into a solution that is stirred on a magnetic stirrer. Nitrogen is introduced into the solution through this needle. The tube was heated at 135 ° C for 4 hours. The pyridine was then removed with nitrogen and the resulting oil heated at 150 ° C for 4 hours. The tube was cooled to room temperature to give 0.045 g of crude product as a white solid. The crude product contained no impurities measurable by thin layer chromatography. The product can be purified by column chromatography on silica gel, using a gradient mixture of ethyl acetate and hexane as eluent, or by recrystallization from a mixture of ethyl acetate and hexane.

Mp = 140-145 ° C (crude);

NMR (300 MHz, CDC1 ₃₎ δ 1.24 (t, J = 7.6 Hz, 3H), 1.72 (m, 2H), 1.94 (m, 2H), 2.16 (m, 4H), 2.66 (q, J = 7.6 Hz , 2H), 2.98 (t, J = 7.0 Hz, 2H), 4.25 (t, J = 7.0 Hz, 2H), 5.60 (quintet, J = 7.7 Hz, 1H), 7.48 (dd, J = 4.9 and

7.8 Hz, 1H), 8.05 (d, J = 8.0 Hz, 1H), 8.75 (dd, J = 1.4 and 4.9 Hz, 1H), 8.9 (d, J = 1.7 Hz, 1H);

Calculated analysis results for C ₁₉ H ₂₂ N ₆ : C, 68.23; H, 6.63;

N, 25.13.

Results: C, 67.39; H, 6.87; N, 24.00.

EXAMPLES 2-18

The reaction of a suitable hydrazide with 1-cyclopentyl-4,5-dihydro-3-ethyl-7-methylthio-1H-pyrazolo [3,4-c] pyridine, analogous to the procedure of Example 1, to give the following compounds of formula I wherein R ^{1 is} ethyl and R ³ cyclopentyl.

Example R ^z T _tel (° C) MW HMRS or % C analysis, % H,% N (Calc.) HMRS or % C analysis, % H,% N (Age) 2 phenyl 333.42 [Μ + Η] 334.2032 [Μ + Η] 334.2032 3 2-furanyl 95-97 323.43 66.85, 6.55, 21.67 67.29, 7.13, 19.56 4 3-methoxy-phenyl 130-2 363.45 69.39, 6.93, 19.27 69.42, 7:30 p.m. 18.13 5 3-tenyl 134-5 353.5 64.55, 6.56, 19.81 64.62, 6.67, 18.57 6 2-Methyl-phenyl 109-12 347.45 72.59, 7.25, 20.16 71.40, 7.38, 19.49 7 2-methoxy-phenyl 132-7 363.47 69.39, 6.93, 19.27 68.61, 6.82, 18.82 8 4-hydroxy-phenyl 251-3 349.44 68.74, 6.63, 20.04 66.86, 6.69, 19.47

9 3-chloro-4- methylthien-2-yl 136-8 387.94 58.82, 5.72, 18.05 58.54, 5.93, 17.88 10 5- (3-methyl pyrazole) 305-6 337.43 [ΜΗ +] 338.2093 [ΜΗ +] 338.2093 11 benzyl 116-7 347.47 [ΜΗ +] 347.2110 [ΜΗ +] 347.2109 12 3-hydroxy-phenyl 240-3 349.45 [ΜΗ +] 350.1981 [ΜΗ +] 350.1981 13 2-hydroxy-3- methylphenyl 147-9 363.47 [ΜΗ +] 364.2137 [ΜΗ +] 364.2137 14 2-hydroxy phenyl 209 349.45 68.33, 6.66, 20.11 68.68, 6.63, 20.04 15 2-Pyridyl 153-5 334.43 MS (m / z) 335 16 a-hydroxy benzyl oil 363.50 MS (m / z) 364 17 3,4-dimethoxy- benzyl 110-7 407.52 [ΜΗ +] 408.2400 [ΜΗ +] 408.2399 18 4-Pyridyl 198-200 334.39 [ΜΗ +] 335.1984 [ΜΗ +] 335.1984

EXAMPLE 19

9-Cyclopentyl-5,6-dihydro-7-ethyl-3- (thien-2-yl) -9H-pyrazolo- [3,4c] -1,2,4-triazolo [4,3-α] pyridine 1 -cyclopentyl-3-ethyl-7-thio-1H-pyrazolo- [3,4-c] -pyridine (0.35 g, 1.4 mmol) was dissolved in anhydrous pyridine (4 mL), dried over a flame in a tube under nitrogen atmosphere. The tube was heated to 70 ° C and 1.5 mL of hydrazine was added. The yellow solution turns pink. The mixture was stirred for 5 minutes and then pyridine and excess hydrazine were removed under reduced pressure to give a pink colored solid. It turns slightly green in vacuo (about 0.1 mm) after half an hour. Anhydrous pyridine (4 mL) and 2-thiophene carbonyl chloride (0.69 g, 4.7 mmol) were then placed in a test tube and stirred for 2 hours. The pyridine was removed under reduced pressure and the residue dissolved in dimethylformamide (4 mL) and heated at reflux for 2 hours. The mixture was cooled to room temperature, washed with water and extracted with ethyl acetate. The aqueous layers were adjusted to pH 12 with 1N NaOH and extracted three times with ethyl acetate. The combined organic extracts are washed with

AND NaOH, water and brine, dried over sodium sulfate and concentrated under reduced pressure. The resulting oil was purified by chromatography on a silica gel column using a gradient mixture of ethyl acetate and hexane as eluent. This gives 304 mg of the title product as a white solid. T i = _the 125-126 ° C (crude);

^X H NMR (300 MHz, CDCl ₃ ) δ 1.25 (t, J = 7.5 Hz, 3H), 1.60-1.74 (m, 2H),

1.9-2.0 (m, 2H), 2.11-2.21 (m, 4H), 2.67 (q, J = 7.6 Hz, 2H), 3.00 (t, J = 7.1 Hz, 2H), 4.30 (t, J = 7.1 Hz) , 2H), 5.60 (quintet, J = 7.7 Hz, 1H),

7.20 (dd, J = 3.9 and 5.1 Hz, 1H), 7.49-7.54 (m, 2H); calculated analysis results for Ci ₈ H ₂ and N ₅ S: C, 63.68; H, 6.42; N, 20.63. Found: C, 63.66; H, 6.19; N, 21.00.

Examples 20-30

Reaction of suitable acid chloride with hydrazine and 1cyclopentyl-3-ethyl-7-thio-4,5,6,7-tetrahydro-1H-pyrazolo [3, Ίο] pyridine, analogous to method 19, to give the following compounds of formula I, wherein R ¹ ethyl and R ³ cyclopentyl.

Example R ^z T _mp (° C) molska mass HRMS or % C analysis, % H,% N (Calc.) HRMS or % C analysis, % H,% N (Age) 20 n-propyl 88-92 299.41 [Μ + Η] 300.2188 [Μ + Η] 300.2188 21 methyl 174-5 271.37 66.39, 7.80, 25.81 66.39, 7.80, 25.81 22 2-chlorophenyl 132-4 367.89 65.29, 6.03, 19.05 65.29, 6.03, 19.05 23 3-chlorophenyl 158 367.89 65.29, 6.03, 19.04 65.29, 6.03, 19.04 24 cyclopentyl oily 325.48 [Μ + Η] 326.2345 [Μ + Η] 326.2345 25 isopropyl oily 299.44 MS (m / z) 300 26 1-methyl- cyclohex-1-yl oily 353.4 [Μ + Η] 354.2658 [Μ + Η] 354.2658 27 2- chloro-pyrid- 3- il 161-3 368.87 61.86, 5.74, 22.79 61.90, 5.94, 23.05 28 2-iodophenyl 145-7 459.34 52.29, 4.83, 15.25 51.64, 5.00, 14.89 29 2-trifluoro- netil phenyl 154-5 401.44 62.83, 5.53, 17.45 61.43, 5.53, 16.74 30 t-butyl 144-5 313.45 68.97, 8.68, 22.34 68.60, 8.88, 22.51

EXAMPLE 31

5,6-Dihydro-7-ethyl-9- (4-trifluorophenyl) -3- (1-methylcyclohex-1-yl) 9H-pyrazolo [3,4-c] -1,2,4-triazolo [4, 3-pyridine

3-ethyl-1 (4-fluorophenyl) -7-thio-4,5,6,7-tetrahydro-1H-pyrazolo [3,4-c] -pyridine (0.092 g) was dissolved in anhydrous pyridine (5 mL) and the solution was heated to 70 ° C. 2 mL of anhydrous hydrazine was added and the yellow solution turned a greyish brown. After 5 minutes, the volatiles can be removed under reduced pressure to give a yellow colored solid. Anhydrous pyridine (5 mL) and 1-methyl cyclohexane carbonyl chloride (0.2 g) were then added. After stirring for 2 hours, the pyridine was removed under reduced pressure and the residue was dissolved in dimethylformamide (5 mL) and heated for 12 hours at reflux temperature. The mixture was cooled to room temperature, washed with water and extracted with ethyl acetate. The combined organic extracts were washed with water and brine, dried over sodium sulfate and concentrated under reduced pressure. The resulting light brown oil was purified by silica gel column chromatography using 1: 2 ethyl acetate: hexane as eluent. This gives 0.09 g of the title product as a pale yellow solid. T _that i = 60-61 ° C (crude); MS (m / z) 380.

Claims (5)

A compound of the formula and pharmaceutically acceptable salts thereof, characterized in that: R ¹ is hydrogen, (C 1 -C ₆ ) alkyl, (C 1 -C ₆ ) alkoxy, (C 1 -C ₆ ) -alkenyl, phenyl, dimethylamino, (C ₃ -C ₆ ) cycloalkyl, (C ₃ -C ₆ ) -cycloalkyl, (C ₁ -C ₃ ) alkyl or (C ₁ -C ₆ ) acyl, wherein the alkyl, phenyl or alkenyl group may be substituted by up to two hydroxy, (C 1 -C ₃ ) alkyl or trifluoromethyl groups or by up to three halogens; R ² and R ³ are each independently selected from hydrogen, (C 1 -C 7) alkyl, (C ₁ -C 7) alkoxy (C 1 -C 7) alkyl, (C ₂ -C ₄ ) alkenyl, (C ₃ -C ₇ ) cycloalkyl, (C ₃ C 1) -cycloalkyl (C 1 -C ₂ ) alkyl, saturated or unsaturated (C 4 -C 7) heterocyclic (CH ₂ ) _n group, where n is 0, 1 or 2, and contains a heteroatom in one or two groups which they are composed of oxygen, sulfur, sulfonyl, nitrogen and NR ⁴ , where R ^{4 is} hydrogen or (C _x - C ₄ ) alkyl; or a group of formula, H where a is an integer between 1 and 5; b and c are 0 or 1; R ⁵ is hydrogen, hydroxy, (C 1 -C 5) alkyl, (C 2 -C 5) alkenyl, (C 1 -C 5) -alkoxy, (C 3 -C 6) cycloalkoxy, halogen, trifluoromethyl, CO2R ⁶ , CONR ⁶ R ⁷ , NR ⁶ R ⁷ , NO 2 or SO ₂ NR ⁶ R ⁷ , wherein R ⁶ and R ^{7 are} each independently selected from hydrogen or (C 3 -C 4) alky; wherein Z is oxygen, sulfur, SO 2, CO or NR ⁸ wherein R ^{8 is} hydrogen or (C 1 -C 4) alkyl; and Y is (C ₁ -C ₅ ) alkylene or (C ₂ -C ₆ ) alkenyl optionally substituted by up to two (C 1 -C ₇ ) alkyl or (C ₃ -C ₇ ) -cycloalkyl groups; wherein each alkyl, alkenyl, cycloalkyl, alkoxyalkyl or heterocyclic group may be substituted by one to fourteen, preferably one to five, of the groups consisting of (C 1 -C ₂ ) alkyl, trifluoromethyl or halogen; and R ⁹ and R ¹⁰ are each independently selected from the group consisting of hydrogen, (C 1 -C ₆ ) alkyl, (C 1 -C ₆ ) alkoxy, (C ₆ -C ₁₀ ) aryl and (C ₆ C 10) aryloxy. A compound according to claim 1, wherein R ^{1 is} methyl, ethyl or isopropyl. 3- (2-chlorophenyl) -9-cyclopentyl-5,6-dihydro-7-ethyl-9H-pyrazolo [3,4c] -1,2,4-triazolo [4,3-a] pyridine; 9-cyclopentyl-5,6-dihydro-7-ethyl-3- (2-iodophenyl) -9H-pyrazolo [3,4c] -1,2,4-triazolo [4,3-a] pyridine; 5,6-Dihydro-7-ethyl-9- (4-fluorophenyl) -3- (1-methylcyclohex-1-yl) -9Hpyrazolo [3,4-c] -1,2,4-triazolo [4,3 -α] pyridine. 3- (t, -butyl) -9-cyclopentyl-5,6-dihydro-7-ethyl-9H-pyrazolo- [3,4-c] 1,2,4-triazolo [4,3-α] pyridine; 9-cyclopentyl-5,6-dihydro-7-ethyl-3- (thien-2-yl) -9H-pyrazolo- [3,4c] -1,2,4-triazolo [4,3-α] pyridine; 3,9-dicyclopentyl-5,6-dihydro-7-ethyl-9H-pyrazolo [3,4-c] -1,2,4triazolo [4,3-α] pyridine; 9-Cyclopentyl-5,6-dihydro-7-ethyl-3- (1-methylcyclohex-1-yl) -9Hpyrazolo [3,4-c] -1,2,4-triazolo [4,3-α] pyridine ; Compound according to claim 1, characterized in that R ^{3 is} (C 1 -C ₆ ) alkyl, (C ₂ -C ₆ ) alkenyl, (C ₃ -C ₇ ) -cycloalkyl, (C ₃ -C ₇ ) cycloalkyl (C 1 -C 5) alkyl or phenyl optionally substituted by one to two groups consisting of hydrogen, hydroxy, (C 1 -C ₅ ) alkyl, (C ₂ -C ₅ ) -alkenyl, (C 1 -C 5) alkoxy, halogen , trifluoromethyl, CO ₂ R ⁶ , CONR ⁶ R ⁷ , wherein each of R ⁶ and R ^{7 is} independently hydrogen or (C 1 -C ₄ ) alkyl. Compound according to claim 1, characterized in that it is selected from the group consisting of: 9-cyclopentyl-5,6-dihydro-7-ethyl-3-phenyl-9H-pyrazolo [3,4-c] -1,2,4triazolo [4,3-α] pyridine; 9-cyclopentyl-5,6-dihydro-7-ethyl-3- (4-pyridyl) -9H-pyrazolo [3,4-c] 1,2,4-triazolo [4,3-α] pyridine; 9-cyclopentyl-5,6-dihydro-7-ethyl-3- (3-tenyl) -9H-pyrazolo [3,4-c] 1,2,4-triazolo [4,3-α] pyridine; 5. Pharmaceutical compositions for (a) treatment of asthma, arthritis, bronchitis, chronic obstructive airways disease, psoriasis, allergic rhinitis, dermatitis and other inflammatory diseases characterized by type IV phosphorodiesterase (PDE) activity, sepsis, septic shock and other diseases such as cachexia involving TNF production; or (b) inhibition of type IV phosphodiesterase and production of TNF-α, characterized in that they contain an effective amount of the compound of claim 1 or its pharmaceutically acceptable salts together with a pharmaceutically acceptable carrier. for Pfizer Inc, 235 New York _A NY Representative: ABSTRACT A compound of the formula wherein R ¹ , R ² , R ³ , R ⁹ and R ¹⁰ are as defined above. The compound of formula I and its pharmaceutically acceptable salts act as phosphodiesterase (PDE) inhibitors of type IV and in the production of tumor necrosis factor (TNF) and in the treatment of asthma, arthritis, bronchitis, chronic obstructive airways disease, psoriasis, allergic rhinitis, dermatitisin other inflammatory diseases diseases characterized by phosphodiesterase (PDE) type IV activity, as well as AIDS, sepsis, septic shock, and other diseases such as cachexia that involve the production of TNF.